G protein- and agonist-bound serotonin 5-HT2A receptor model activated by steered molecular dynamics simulations
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G protein- and agonist-bound serotonin 5-HT2A receptor model activated by steered molecular dynamics simulations. / Ísberg, Vignir; Balle, Thomas; Sander, Tommy; Jørgensen, Flemming Steen; Gloriam, David Erik Immanuel.
I: Journal of Chemical Information and Modeling, Bind 51, Nr. 2, 28.02.2011, s. 315-325.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - G protein- and agonist-bound serotonin 5-HT2A receptor model activated by steered molecular dynamics simulations
AU - Ísberg, Vignir
AU - Balle, Thomas
AU - Sander, Tommy
AU - Jørgensen, Flemming Steen
AU - Gloriam, David Erik Immanuel
PY - 2011/2/28
Y1 - 2011/2/28
N2 - A 5-HT(2A) receptor model was constructed by homology modeling based on the ß(2)-adrenergic receptor and the G protein-bound opsin crystal structures. The 5-HT(2A) receptor model was transferred into an active conformation by an agonist ligand and a G(aq) peptide in four subsequent steered molecular dynamics (MD) simulations. The driving force for the transformation was the addition of several known intermolecular and receptor interhelical hydrogen bonds enforcing the necessary helical and rotameric movements. Subsquent MD simulations without constraints confirmed the stability of the activated receptor model as well as revealed new information about stabilizing residues and bonds. The active 5-HT(2A) receptor model was further validated by retrospective ligand screening of more than 9400 compounds, whereof 182 were known ligands. The results show that the model can be used in drug discovery for virtual screening and structure-based ligand design as well as in GPCR activation studies.
AB - A 5-HT(2A) receptor model was constructed by homology modeling based on the ß(2)-adrenergic receptor and the G protein-bound opsin crystal structures. The 5-HT(2A) receptor model was transferred into an active conformation by an agonist ligand and a G(aq) peptide in four subsequent steered molecular dynamics (MD) simulations. The driving force for the transformation was the addition of several known intermolecular and receptor interhelical hydrogen bonds enforcing the necessary helical and rotameric movements. Subsquent MD simulations without constraints confirmed the stability of the activated receptor model as well as revealed new information about stabilizing residues and bonds. The active 5-HT(2A) receptor model was further validated by retrospective ligand screening of more than 9400 compounds, whereof 182 were known ligands. The results show that the model can be used in drug discovery for virtual screening and structure-based ligand design as well as in GPCR activation studies.
KW - Former Faculty of Pharmaceutical Sciences
U2 - 10.1021/ci100402f
DO - 10.1021/ci100402f
M3 - Journal article
C2 - 21261291
VL - 51
SP - 315
EP - 325
JO - Journal of Chemical Information and Modeling
JF - Journal of Chemical Information and Modeling
SN - 1549-9596
IS - 2
ER -
ID: 33097003